Protein folding quality control is an inherently important biological problem with immediate relevance to human health. With increased human lifespan is the increased risk of neurodegenerative diseases of aging many of which are associated with the expression of misfolded and damaged proteins. To examine whether this imbalance in protein homeostasis is a common basis for these diseases, we developed a C. elegans model for polyglutamine (polyQ) disease. Our results show that polyQ aggregation and toxicity exhibit a dependence on polyQ-length that can be suppressed by specific chaperones and mutations that enhance longevity. We then used a genome-wide RNAi screen to identify five classes of genetic modifiers that regulate polyQ aggregation. Based on these results, we propose to test the hypothesis that neurodegenerative disease-associated proteins exhibit a common "proteotoxicity". This will be addressed by establishing comparable transgenic lines expressing polyQ proteins, Huntingtin, Ataxins 1 and 3, mutant SOD1, and prions in neurons and non-neuronal cells. This comprehensive approach should reveal features on the basis of cell-type sensitivity of protein damage and the effects of aging on the aggregation phenotype. The studies in this proposal will address questions on the biochemical events that lead to the appearance of misfolded species and aggregates, the molecular events and cellular consequences of protein misfolding, the role of chaperone networks and the proteasome in this process, and identification of genetic modifiers including aging that influences the appearance and fate of damaged proteins. The outcome of these studies will address whether distinct aggregation-prone proteins result in a common "proteotoxicity" that are regulated by the same or distinct components of the protein folding quality control "proteome". We propose that C. elegans offers a unique opportunity to understand how these various processes are integrated, the basis for differences between neuronal and non-neuronal cells, and the role of damaged proteins on homeostasis and aging.